Lifespan regulation is a complex process that is coordinated by divergent pathways, including DNA damage, oxidative stress, and metabolic networks (Houtkooper et al., 2010, Cell 142, 9). It has been established by gain- and loss-of-function studies, especially in C. elegans and D. melanogaster, but also in mice, that caloric excess pathways, such as the insulin/IGF1 signaling pathway and the mammalian target of rapamycin (mTOR), decrease lifespan (Harrison et al., 2009, Nature 460, 392-395; Bjedov et al., 2010, Cell Metab 11, 35; Zid et al., 2009, Cell 139, 149; Selman et al., 2009, Science 326, 140), whereas the caloric restriction pathways, for instance AMP-activated protein kinase (AMPK) and sirtuins, tend to increase lifespan (Mair et al., 2011, Nature 470, 404-408; Anisimov et al., 2008, Cell Cycle 7, 2769). Whether or not such genes also contribute to natural lifespan is, however, not understood.
Additionally, in mouse, AMPK has been connected with sirtuin 1 (SIRT1) (Canto et al., 2009, Nature 458, 1056-1060) and peroxisome proliferator-activated receptor-γ coactivator (PGC-1)-αsignaling (Canto et al., 2009, supra; Canto et al., 2010, Cell Metab 11, 213-219) consolidating the link of this system with mitochondrial metabolism, notably mitochondrial respiration. It is still debated, however, how mitochondrial function impacts aging, as both inhibiting and stimulating mitochondrial metabolism seems to enhance lifespan (discussed in Houtkooper et al., 2010, supra; Kenyon, 2010, Nature 464, 504-512).
Aging and the diseases associated with it are a heavy burden on society. The current increase in life expectancy not only impacts on our social systems, but also goes hand in hand with the emergence of common chronic diseases, including those of the nervous, immune, and cardio-metabolic systems, which often reach epidemic proportions. In this respect it is important to understand the natural aging process and to elucidate where lifestyle and/or pharmacological interventions can have an impact. In recent years, many novel therapeutic options have been suggested to prevent aging-associated diseases. Although some of these pharmaceutical interventions were shown to extend lifespan, even in mammals (Harrison et al., 2009, supra; Pearson et al., 2008, Cell Metab 8, 157-168), there is still a need for identification of novel compounds that have the ability to increase lifespan and, thus, be useful for delaying aging and/or preventing or treating age-related diseases and disorders.
The present invention solves this problem by identifying a novel target that functions as a longevity regulator and is conserved from Caenorhabditis elegans to mammals.